Targeting cardiac myocyte Na+-K+ pump function with β3 adrenergic agonist in rabbits and patients with severe congestive heart failure

Background Raised intracellular Na+ impairs cardiac contractility in severe heart failure (HF). β3 adrenoceptor (β3 AR) agonists activate cardiomyocyte Na+-K+ pump-mediated Na+ export. Treatment with a selective β3 AR agonist in patients with severely reduced left ventricular ejection fraction (LVEF) and stable HF improves LVEF. We examined effects of β3 AR agonists on Na+-K+ pump function in experimental severe HF characterized by organ congestion and, in parallel, the clinical response in human treatment-refractory worsening chronic HF (WCHF). Methods The circumflex coronary artery was ligated in rabbits to induce HF. Treatment with β3 AR agonists was started 2 weeks later and effects on congestive signs were assessed, including ascites and the primary outcome, lung: body weight ratio. Na+-K+ pump current was measured in voltage-clamped myocytes from non-infarcted myocardium. The β3 AR agonist mirabegron was prescribed off-label to patients hospitalized with advanced HF (stage D) that was refractory to maximally tolerated guideline-directed treatment and intravenous furosemide, with or without inotropes, as assessed by ≥2 cardiologists. Results Rabbits developed severe HF with markedly increased lung:body weight ratio and ascites. Na+-K+ pump current was decreased in myocytes from rabbits with HF. β3 AR agonists eliminated pump inhibition, significantly reduced lung:body weight ratio and prevalence of ascites. Mirabegron was given to 9 patients aged 74 ± 7 years (mean ± SD) with advanced HF. LVEF was 26 ± 5%. Signs and symptoms improved within 1-2 days of treatment. Mirabegron was well-tolerated and improvement of ≥1 NYHA Class maintained by all early after discharge. One patient died from HF at 16 months, 4 died from other causes at 2 – 30 months and 4 remain alive at 30 ± 5 months with NYHA Class II symptoms. Conclusion Treatment with β3 AR agonist in a pre-clinical model of severe HF can reverse Na+-K+ pump inhibition and improve organ congestion implicating pump inhibition as a reversible myocardial dysfunction that is a useful treatment target. The changed in-hospital clinical trajectory and a more favourable post-discharge course than expected in advanced HF, suggests efficacy of β3 AR agonist shown in the animal model might translate into efficacy in advanced human HF.